A cascade of neuronal and glial transformations are triggered by photoreceptor or retinal pigmented epithelium degenerations. These remodeling processes, initiated prior to the death of photoreceptors and persisting after they are lost, encompass over 30 distinct aberrations including altered glutamate receptor expression, anomalous neurite and synapse formation, anomalous signaling, intraretinal migration and emigration, and neuronal death. Remodeling stands in the way of many proposed therapies. Our program focuses on discovering key remodeling mechanisms for drug discovery, intervention and retinal stabilization in retinitis pigmentosa (RP) and AMD. We will attempt this through three aims: (1) analysis of early cone and bipolar cell deconstruction;(2) exploration of mechanisms of corruptive intrinsic non-visual self-signaling and retinoid-induced axonogenesis;and (3) characterizing remodeling in AMD / AMD-like retinal degenerations. This research fuses advanced cell profiling methods of excitation mapping, computational molecular phenotyping (CMP), and traditional protein mapping with a selection of RP/AMD animal models (guanylate cyclase knockout mice, light-induced retinal degeneration mice, Pde6brd1 mice, rhodopsin P347L transgenic rabbits). We seek definition of key molecular pathologies (e.g. MAPK pathways in cones and bipolar cells, aberrant retinoid processing;emigrant cell profiles) that may serve as drug targets. The goal is to preserve RP and AMD retinas for genetic, molecular, cellular or bionic rescue. Relevance. Loss of neuronal structure and function in remodeling is likely the earliest cause of vision loss in retinal degenerations. These anomalies progressively impede development of therapies. Discovering the mechanisms of the many forms of remodeling may facilitate neuroprotective drug development or identification of existing drugs. PUBLIC HEALTH RELEVANCE: Loss of neuronal structure and function in remodeling is likely the earliest cause of vision loss in retinal degenerations. These anomalies progressively impede development of therapies. Discovering the mechanisms of the many forms of remodeling may facilitate neuroprotective drug development or identification of existing drugs.